Technische Universität München

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Narcotics are naturally occurring, semisynthetic or synthetic drugs which bind to opioid receptors to produce physiological effects. Most of the current available opioid analgesics exert their analgesic and adverse effects primarily through the opioid mu-receptors. The clinical use of the opioids is limited by serious side effects such as respiratory depression, development of tolerance, and psychological and physical dependence. Excessive dosing of opioids may results in significant toxicity. The toxic and lethal doses depend greatly on the individual's tolerance to the drug, thus the usual dose for an addict is dangerous for a nonuser or may be dangerous for the same addict after several days of abstinence because of the rapid diminution in tolerance. The main toxic effects are respiratory depression, coma and death.
The respiratory system is the commonest site of complications of opioid overdosage. The effects include respiratory depression, acute pulmonary edema, bronchospasm, aspiration of vomit and aspiration pneumonia. Death from opioid overdose is usually due to respiratory failure.
Respiration is controlled through medullary respiratory centers with peripheral input from chemoreceptors and other sources. Opioid administration leads to respiratory depression because it produces inhibition at the chemoreceptors via mu-opioid receptors and in the medulla via mu- and delta-receptors. Reduction in the ventilation, increase in the resting CO2 levels, and a rise in the CO2 threshold are observed in healthy subjects after opioid administration. The effect on respiration depends on the type of the opioid agonist. For example, in opioid-naïve volunteers morphine and fentanyl (pure agonists) produce dose-dependent depression of minute ventilation with apnea at high dose levels, but buprenorphine (partial agonist) causes dose-independent respiratory depression with a ceiling effect at higher doses. Independent of the type of the opioid, the opioid–induced respiratory depression leading to hypoventilation and hypoxemia may produce irreversible neurologic injury and this combined with the central nervous system depression may result in death. Concurrent use of opioids with alcohol or benzodiazepines increases the risk of respiratory arrest. Glutamate and gamma-aminobutyric acid (GABA) are respectively the major excitatory and inhibitory neurotransmitters that mediate the control of respiration. This explains the potential for interaction of opioids with benzodiazepines and alcohol. Both benzodiazepines and alcohol facilitate the inhibitory effect of GABA, while alcohol also decreases the excitatory effect of glutamate on respiration.
Opioid overdose may also induce noncardiogenic pulmonary edema and bronchospasm. Pulmonary edema is almost universal occurrence in fatal overdose. Direct toxic effects or anaphylactoid reactions have been suggested as possible mechanisms of the opioid-induced noncardiogenic pulmonary edema. Opioids have a histamine-releasing effect, which can also cause constriction of bronchial smooth muscles and induce bronchospasm and asthma exacerbation. In addition, opioids can cross the placenta and can be found in breast milk. Therefore, neonatal respiratory depression can occur in babies born to mothers addicted to opioids.
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